Please use this identifier to cite or link to this item: https://doi.org/10.1038/s41467-018-05644-0
Title: Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1
Authors: Xu, X
Li, Y
Bharath, S.R
Ozturk, M.B
Bowler, M.W
Loo, B.Z.L
Tergaonkar, V 
Song, H 
Keywords: DNA fragment
immunoglobulin enhancer binding protein
protein p52
transcription factor Ets 1
disulfide
DNA
ETS1 protein, human
immunoglobulin enhancer binding protein
protein binding
telomerase
TERT protein, human
transcription factor Ets 1
cancer
chemical binding
complexity
crystal structure
DNA
inhibition
mutation
reactivation
Article
binding affinity
crystal structure
DNA binding
ETS domain
gene activation
HEK293T cell line
human
human cell
immunoprecipitation
multiple cancer
promoter region
protein protein interaction
signal transduction
TERT gene
transactivation
binding site
chemistry
enzyme activation
Escherichia coli
genetics
HEK293 cell line
metabolism
protein multimerization
X ray crystallography
Binding Sites
Crystallography, X-Ray
Disulfides
DNA
Enzyme Activation
Escherichia coli
HEK293 Cells
Humans
NF-kappa B
NF-kappa B p52 Subunit
Promoter Regions, Genetic
Protein Binding
Protein Multimerization
Proto-Oncogene Protein c-ets-1
Signal Transduction
Telomerase
Issue Date: 2018
Publisher: Nature Publishing Group
Citation: Xu, X, Li, Y, Bharath, S.R, Ozturk, M.B, Bowler, M.W, Loo, B.Z.L, Tergaonkar, V, Song, H (2018). Structural basis for reactivating the mutant TERT promoter by cooperative binding of p52 and ETS1. Nature Communications 9 (1) : 3183. ScholarBank@NUS Repository. https://doi.org/10.1038/s41467-018-05644-0
Abstract: Transcriptional factors ETS1/2 and p52 synergize downstream of non-canonical NF-?B signaling to drive reactivation of the ?146C>T mutant TERT promoter in multiple cancer types, but the mechanism underlying this cooperativity remains unknown. Here we report the crystal structure of a ternary p52/ETS1/?146C>T TERT promoter complex. While p52 needs to associate with consensus ?B sites on the DNA to function during non-canonical NF-?B signaling, we show that p52 can activate the ?146C>T TERT promoter without binding DNA. Instead, p52 interacts with ETS1 to form a heterotetramer, counteracting autoinhibition of ETS1. Analogous to observations with the GABPA/GABPB heterotetramer, the native flanking ETS motifs are required for sustained activation of the ?146C>T TERT promoter by the p52/ETS1 heterotetramer. These observations provide a unifying mechanism for transcriptional activation by GABP and ETS1, and suggest that genome-wide targets of non-canonical NF-?B signaling are not limited to those driven by consensus ?B sequences. © 2018, The Author(s).
Source Title: Nature Communications
URI: https://scholarbank.nus.edu.sg/handle/10635/174210
ISSN: 2041-1723
DOI: 10.1038/s41467-018-05644-0
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